Nanoparticulate dispersions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate

ABSTRACT

Disclosed are solid dose nanoparticulate compositions comprising a poorly soluble active agent, at least one polymeric surface stabilizer, and dioctyl sodium sulfosuccinate (DOSS). The solid dose compositions exhibit superior redispersibility of the nanoparticulate composition upon administration to a mammal, such as a human or animal. The invention also describes methods of making and using such compositions.

This application is a continuation of Ser. No. 09/666,539 filed Sep. 21,2000.

FIELD OF THE INVENTION

The present invention is directed to solid dose nanoparticulatecompositions having a synergistic combination of at least one polymericsurface stabilizer and dioctyl sodium sulfosuccinate (DOSS). The soliddose compositions exhibit superior redispersion of the nanoparticulatecomposition either upon administration to a mammal, such as a human oranimal, or reconstitution in an aqueous electrolyte solution.

BACKGROUND OF THE INVENTION

A. Background Regarding Nanoparticulate Compositions

Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684(“the '684 patent”), are particles consisting of a poorly solubletherapeutic or diagnostic agent having adsorbed onto the surface thereofa non-crosslinked surface stabilizer. This invention is an improvementover that disclosed in the '684 patent, as the '684 patent does notdescribe the use of synergistic combinations of polymeric surfacestabilizers and DOSS in solid dose compositions.

Prior U.S. patents teach the use of DOSS as a primary or secondarysurface stabilizer for nanoparticulate compositions. See e.g., U.S. Pat.No. 5,145,684, for “Surface Modified Drug Nanoparticles;” U.S. Pat. No.5,302,401, for “Method to Reduce Particle Size Growth DuringLyophilization;” U.S. Pat. No. 5,318,767, for “X-Ray ContrastCompositions Useful in Medical Imaging;” U.S. Pat. No. 5,336,507, for“Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” U.S.Pat. No. 5,346,702, for “Use of Non-Ionic Cloud Point Modifiers toMinimize Nanoparticulate Aggregation During Sterilization;” U.S. Pat.No. 5,399,363, for “Surface Modified Anticancer Nanoparticles;” U.S.Pat. No. 5,401,492, for “Water-Insoluble Non-Magnetic ManganeseParticles as Magnetic Resonance Enhancement Agents;” U.S. Pat. No.5,429,824, for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” U.S.Pat. No. 5,451,393, for “X-Ray Contrast Compositions Useful in MedicalImaging;” U.S. Pat. No. 5,466,440, for “Formulations of OralGastrointestinal Diagnostic X-Ray Contrast Agents in Combination withPharmaceutically Acceptable Clays;” U.S. Pat. No. 5,470,583, for “Methodof Preparing Nanoparticle Compositions Containing Charged Phospholipidsto Reduce Aggregation;” U.S. Pat. No. 5,494,683, for “Surface ModifiedAnticancer Nanoparticles;” U.S. Pat. No. 5,503,723, for “Isolation ofUltra Small Particles;” U.S. Pat. No. 5,510,118, for “Process forPreparing Therapeutic Compositions Containing Nanoparticles;” U.S. Pat.No. 5,543,133, for “Process of Preparing X-Ray Contrast CompositionsContaining Nanoparticles;” U.S. Pat. No. 5,552,160, for “SurfaceModified NSAID Nanoparticles;” U.S. Pat. No. 5,560,931, for“Formulations of Compounds as Nanoparticulate Dispersions in DigestibleOils or Fatty Acids;” U.S. Pat. No. 5,560,932, for “Microprecipitationof Nanoparticulate Pharmaceutical Agents;” U.S. Pat. No. 5,571,536, for“Formulations of Compounds as Nanoparticulate Dispersions in DigestibleOils or Fatty Acids;” U.S. Pat. No. 5,580,579, for “Site-SpecificAdhesion Within the GI Tract Using Nanoparticles Stabilized by HighMolecular Weight, Linear Poly(ethylene Oxide) Polymers;” U.S. Pat. No.5,587,143, for “Butylene Oxide-Ethylene Oxide Block CopolymerSurfactants as Stabilizer Coatings for Nanoparticulate Compositions;”U.S. Pat. No. 5,593,657, for “Novel Barium Salt Formulations Stabilizedby Non-Ionic and Anionic Stabilizers;” U.S. Pat. No. 5,628,981, for“Improved Formulations of Oral Gastrointestinal Diagnostic X-RayContrast Agents and Oral Gastrointestinal Therapeutic Agents;” U.S. Pat.No. 5,665,331, for “Co-Microprecipitation of NanoparticulatePharmaceutical Agents with Crystal Growth Modifiers;” U.S. Pat. No.5,716,642, for “Microprecipitation of Nanoparticulate PharmaceuticalAgents Using Surface Active Material Derived from Similar PharmaceuticalAgents;” U.S. Pat. No. 5,718,919, for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” U.S. Pat. No. 5,747,001, for “AerosolsContaining Beclomethasone Nanoparticle Dispersions;” U.S. Pat. No.5,834,025, for “Reduction of Intravenously Administered NanoparticulateFormulation Induced Adverse Physiological Reactions;” U.S. Pat. No.6,045,829, for “Nanocrystalline Formulations of Human ImmunodeficiencyVirus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;”and U.S. Pat. No. 6,068,858, for “Methods of Making NanocrystallineFormulations of Human Immunodeficiency Virus (HIV) Protease InhibitorsUsing Cellulosic Surface Stabilizers.” In addition, several publishedinternational applications teach the usefulness of DOSS as a primary orsecondary surface stabilizer for nanoparticulate compositions. See e.g.,WO 98/35666, for “Formulations of Nanoparticle Naproxen Tablets;” WO00/18374, for “Controlled Release Nanoparticulate Compositions;” WO96/25918, for “Aerosols Containing Nanoparticulate Dispersions;” and WO00/27363, for “Aerosols Comprising Nanoparticle Drugs.”

Prior art patents also teach the use of DOSS as a cloud point modifierfor nanoparticulate surface stabilizers. See e.g., U.S. Pat. No.5,298,262, for “Use of Ionic Cloud Point Modifiers to Prevent ParticleAggregation During Sterilization;” U.S. Pat. No. 5,326,552, for “NovelFormulation for Nanoparticulate X-Ray Blood Pool Contrast Agents UsingHigh Molecular Weigh Non-ionic Surfactants;” U.S. Pat. No. 5,346,702,for “Use of Non-Ionic Cloud Point Modifiers to Minimize NanoparticulateAggregation During Sterilization;” U.S. Pat. No. 5,352,459, for “Use ofPurified Surface Modifiers to Prevent Particle Aggregation DuringSterilization;” U.S. Pat. No. 5,447,710, for “Method for MakingNanoparticulate X-Ray Blood Pool Contrast Agents Using High MolecularWeight Non-Ionic Surfactants;” U.S. Pat. No. 5,565,188, for“Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;”U.S. Pat. No. 5,665,330, for “Dual Purpose Diagnostic/Therapeutic AgentHaving a Tri-Iodinated Benzoyl Group Linked to a Coumarin.”

And several prior art references teach the use of DOSS innanoparticulate compositions as both a surface stabilizer and as a cloudpoint modifier for a primary surface stabilizer. See e.g., U.S. Pat. No.5,466,433, for “Polyiodinated Aroyloxy Esters;” U.S. Pat. No. 5,472,683,for “Nanoparticle Mixed Carbamic Anhydrides as X-Ray Contrast Agents forBlood Pool and Lymphatic System Imaging;” U.S. Pat. No. 5,500,204, for“Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for BloodPool and Lymphatic System Imaging;” U.S. Pat. No. 5,521,218, for“Nanoparticulate Iododipamide Derivatives for Use as X-Ray ContrastAgents;” U.S. Pat. No. 5,525,328, for “Nanoparticulate DiagnosticDiatrizoxy Ester X-Ray Contrast Agents for Blood Pool and LymphaticSystems Imaging;” U.S. Pat. No. 5,534,270, for “Method of PreparingX-Ray Contrast Compositions Containing Nanoparticles;” U.S. Pat. No.5,573,749, for “Nanoparticulate Diagnostic Mixed Carboxylic Anhydridesas X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;”U.S. Pat. No. 5,573,750, for “Diagnostic Imaging X-Ray Contrast Agents;”U.S. Pat. No. 5,603,916, for “3,5-Bis-[AlkanoylAmino]-2,4,6-Triiodobenzyl Esters;” U.S. Pat. No. 5,643,552, for“Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray ContrastAgents for Blood Pool and Lymphatic System Imaging;” U.S. Pat. No.5,668,196, for “3-Amido-Triiodophenyl Esters as X-Ray Contrast Agents;”and U.S. Pat. No. 5,670,136, for“2,4,6-Triiodo-5-Substituted-Amino-Isophthalate Esters Useful as X-RayContrast Agents for Medical Diagnostic Imaging.”

U.S. Pat. No. 5,585,108, for “Formulations of Oral GastrointestinalTherapeutic Agents in Combination with Pharmaceutically AcceptableClays,” claims a nanoparticulate dispersion including, inter alia, awater-insoluble particulate drug, a surfactant which can be a polymericstabilizer, such as hydroxypropyl methylcellulose, a pharmaceuticallyacceptable clay, and a secondary stabilizer, such as DOSS or sodiumlauryl sulfate. See col. 7 of the patent. This reference differs fromthe present invention in that it is directed to a nanoparticulatedispersion, and not a solid dose nanoparticulate formulation.

U.S. Pat. No. 5,298,262, for “Use of Ionic Cloud Point Modifiers toPrevent Particle Aggregation During Sterilization,” describes the use ofDOSS in a nanoparticulate composition as an anionic surfactant useful inraising the cloud point of a surface stabilizer. According to the '262patent, by raising the cloud point of the surface stabilizer of ananoparticulate composition, the composition can be heat sterilizedwithout producing particle aggregation because of the exposure toelevated temperatures. Liquid compositions are heat sterilized, notpowders. This is because sterile products are not manufactured for oraladministration because of the cost, complexity, etc. Thus, this patentdoes not teach or suggest the use of DOSS in a solid dose formulation toincrease redispersion of the nanoparticulate composition uponadministration to a mammal, such as a human or animal, or reconstitutionin an aqueous electrolyte solution.

Finally, U.S. Pat. No. 5,518,738, for “Nanoparticulate NSAIDCompositions,” describes a nanoparticulate solid dose of an NSAID havinga film of polyvinylpyrrolidone (PVP), hygroscopic sugar, and sodiumlauryl sulfate adsorbed on the surface of the drug. In the examples ofthis patent, solid films of the nanoparticulate composition with variousredispersants are prepared, including DOSS. In contrast to the presentinvention, the '738 patent teaches that a solid film of ananoparticulate drug, DOSS, and PVP shows'extremely poorredispersibility. Thus, this reference teaches away from the presentinvention.

Many of the prior art patents listed above also teach the usefulness ofpolymeric surface stabilizers for nanoparticulate compositions, such ashydroxypropyl cellulose, hydroxypropyl methyl cellulose, andpolyvinylpyrrolidone.

However, the prior art does not teach or suggest the use of synergisticcombinations of polymeric surface stabilizers and DOSS in solid dosecompositions of nanoparticulate active agents. Nor does the prior artteach or suggest that such synergistic compositions can result insuperior redispersion of the nanoparticulate composition uponadministration to a mammal, such as a human or animal, or reconstitutionin an aqueous electrolyte solution.

B. Background Regarding DOSS

DOSS is an anionic surfactant commercially available from a variety ofsources, including Chemax Inc. (Greenville, S.C.), Finetex Inc. (ElmwoodPark, N.J.), R. W. Greeff & Co. (Greenwich, Conn.), McIntyre Group Ltd.(Chicago, Ill.), Penta Mfg. Co. (Livingston, N.J.), Rhone-Poulenc Inc.Specialty Chemicals Div., (Cranbury, N.J.), RTD Chemicals Corp.(Hackettown, N.J.), Scher Chemicals Inc. (Clifton, N.J.), SpectrumQuality Products Inc. (Gardena, Calif.), Thornley Co. Inc. (Wilmington,Del.), and Van Waters & Rogers (Kirkland, Wash.). It has the chemicalformula C₂₀H₃₇O₇S.Na and the following structure:

DOSS is a widely used wetting agent and dispersant. It is a white,waxlike, plastic solid added to powdered gelatins, drink mixes, andcocoas to make them dissolve more quickly and completely in liquids. Itis also used as a stabilizer in pharmaceuticals, chewing gums, andcanned milks, and is added to shampoos, bath products, and skincleansers. While the U.S. Food and Drug Administration (FDA) limits theamount of DOSS that can be used in food and drug products, it stillrates the compound generally recognized as safe (GRAS). 21 C.F.R.§172.810.

There is a need in the art for solid dose nanoparticulate compositionsexhibiting superior redispersion of the nanoparticulate composition uponadministration to a mammal, such as a human or animal, or reconstitutionin an aqueous electrolyte solution. The present invention satisfies thisneed.

SUMMARY OF THE INVENTION

The present invention is directed to the surprising and unexpecteddiscovery that solid dose nanoparticulate compositions comprising atleast one polymeric surface stabilizer and DOSS exhibit superiorredispersion of the nanoparticulate composition upon administration to amammal, such as a human or animal, or reconstitution in an aqueouselectrolyte solution. The solid dose nanoparticulate compositionscomprise at least one poorly soluble active agent, at least onepolymeric surface stabilizer adsorbed to the surface of the activeagent, and DOSS.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a solid dose nanoparticulate composition of theinvention. The pharmaceutical composition comprises at least one poorlysoluble active agent, at least one polymeric surface stabilizer adsorbedto the surface of the drug, DOSS, and a pharmaceutically acceptablecarrier, as well as any desired excipients.

This invention further discloses methods of making a nanoparticulatecomposition having at least one polymeric surface stabilizer adsorbed onthe surface of the active agent and DOSS. Such a method comprisescontacting a poorly soluble nanoparticulate active agent with at leastone polymeric surface stabilizer and DOSS under time and conditionssufficient to provide a nanoparticle active agent/surfacestabilizer/DOSS composition. Some or all of the polymeric surfacestabilizers and DOSS can be contacted with the active agent eitherbefore, during, or after size reduction of the active agent.

The present invention is further directed to methods of treatmentcomprising administering to a mammal in need a therapeutically effectiveamount of a nanoparticulate composition according to the invention.

Both the foregoing general description and the following detaileddescription are exemplary and explanatory and are intended to providefurther explanation of the invention as claimed. Other objects,advantages, and novel features will be readily apparent to those skilledin the art from the following detailed description of the invention.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Shows the % redispersion in an electrolyte solution, as afunction of the concentration of the electrolyte solution, for a spraydried nanoparticulate MAP kinase inhibitor composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the surprising and unexpecteddiscovery that solid dose nanoparticulate compositions having at leastone polymeric surface stabilizer and DOSS exhibit dramatically superiorredispersion of the nanoparticulate composition upon administration to amammal, such as a human or animal, or upon reconstitution of a drypowder prepared from a nanoparticulate composition in an aqueouselectrolyte solution. The electrolyte concentration should berepresentative of physiological conditions found in the human body.Representative electrolyte solutions can be, but are not limited to,0.1, 0.01, or 0.001 N HCL, and/or 0.1, 0.01, or 0.001 M NaCl, andcombinations thereof. Of these electrolyte solutions, 0.01 N HCl, 0.1 MNaCl, and combinations thereof are most representative of humanphysiological conditions.

Prior to the present invention, liquid dispersions and solid dose formsof nanoparticulate compositions were known. One frequent problem ofprior art solid dose nanoparticulate compositions was that uponadministration to a mammal, such as a human or animal, thenanoparticulate composition would not redisperse, and thus the soliddose composition would lose the benefits afforded by formulating thecomposition into a nanoparticulate form. This is because nanoparticulatecompositions benefit from the small particle size of the active agent;if the active agent does not redisperse into the small particle sizesupon administration, then “clumps” or agglomerated drug particles areformed. With the formation of such agglomerated particles, thebioavailability of the composition drops dramatically below thatobserved with the liquid dispersion form of the drug.

Most drugs are marketed in a solid dose form, such as a tablet, capsule,etc. This is because such dosage forms are easy to store and transport.In addition, such dosage forms are easily marketed. Patient complianceis high, as compared with injectable forms of drugs. Thus, it iscritical to develop solid dose forms of nanoparticulate compositionswhich exhibit the same benefits observed with the liquid dispersion formof the compositions.

It was discovered that solid dose nanoparticulate compositions having atleast one polymeric surface stabilizer and DOSS exhibit dramaticredispersion of the nanoparticulate composition upon administration to amammal, such as a human or animal, or reconstitution in an aqueouselectrolyte solution. DOSS or polymeric stabilizers alone cannot producehighly redispersible solid dose nanoparticulate compositions. Incombination, however, the two compounds exhibit a synergistic effect ofstabilizing the active agent and resulting in dramatic redispersion ofthe solid dose nanoparticulate composition upon administration to amammal, such as a human or animal, or reconstitution in an aqueouselectrolyte solution.

Another benefit of the invention is that DOSS is highly tolerated by thehuman body, in contrast to other dispersants such as SLS, for which thehuman body has a low tolerance. DOSS can be given to humans in largedoses on a chronic basis, as the FDA has approved the use of DOSS as astool softener at doses of up to 500 mg/daily for adults, and inchildren over 6 months old up to 75 mg/day. See Handbook ofPharmaceutical Excipients, Third Edition, p. 189 (AmericanPharmaceutical Association, 2000). The dosage of DOSS employed in thepresent invention is below the threshold amount which produces laxativeeffects.

The combination of DOSS and a polymeric surface stabilizer was tested ona wide variety of drugs, including Mitogen-Activated protein (MAP)kinase inhibitor, an analgesic, and an angiogenesis inhibitor. Thus, thephenomenon of high redispersibility is not limited to a specific drug ordrug class. However, the phenomenon is limited to nanoparticulatecompositions comprising at least one polymeric surface stabilizer andDOSS. Other types of surface stabilizers formulated with DOSS, such asampiphilic stabilizers having hydrophobic and hydrophilic ends, have notbeen found to produce solid dose compositions having comparableredispersion properties.

A. Nanoparticulate Compositions

The nanoparticulate compositions of the invention comprise ananoparticulate active agent, such as a drug, having at least onepolymeric surface stabilizer adsorbed on the surface thereof and DOSS.The nanoparticulate active agent compositions, comprising ananoparticulate active agent and at least one polymeric surfactant, havean effective average particle size prior to incorporation in a soliddose form of less than about 1 micron, less than about 800 nm, less thanabout 600 nm, less than about 400 nm, and less than about 200 nm.

Upon administration to a mammal, such as a human or animal, orreconstitution in an electrolyte solution, the solid dosenanoparticulate composition redisperses such that 960% of the activeagent particles have a particle size of less than about (1) 5 microns,when the nanoparticulate dispersion, prior to incorporation into a soliddose form, has an effective average particle size of less than about 1micron; (2) 4 microns, when the nanoparticulate dispersion, prior toincorporation into a solid dose form, has an effective average particlesize of less than about 800 nm; (3) 3 microns, when the nanoparticulatedispersion, prior to incorporation into a solid dose form, has aneffective average particle size of less than about 600 nm; (4) 2microns, when the nanoparticulate dispersion, prior to incorporationinto a solid dose form, has an effective average particle size of lessthan about 400 nm; and (5) 1 micron, when the nanoparticulatedispersion, prior to incorporation into a solid dose form, has aneffective average particle size of less than about 200 nm.

1. Drug Particles

The nanoparticles of the invention comprise a therapeutic or diagnosticagent, collectively referred to as a “drug,” which is poorly soluble inat least one medium. By “poorly soluble” it is meant that the drug has asolubility in the liquid dispersion medium of less than about 10 mg/mL,and preferably of less than about 1 mg/mL. A therapeutic agent can be apharmaceutical agent, including biologics such as proteins, peptides,and nucleotides, or a diagnostic agent, such as a contrast agent,including x-ray contrast agents. The drug is preferably present in anessentially pure form, is dispersible in at least one liquid medium, andexists either as a discrete, crystalline phase, or as an amorphousphase. The crystalline phase differs from a non-crystalline or amorphousphase which results from precipitation techniques, such as thosedescribed in EP Patent No. 275,796.

The drug can be selected from a variety of known classes of drugs,including, for example, proteins, peptides, nucleotides, anti-obesitydrugs, nutriceuticals, corticosteroids, elastase inhibitors, analgesics,anti-fungal, oncology therapies, anti-emetics, analgesics,cardiovascular agents, anti-inflammatory agents, anthelmintics,anti-arrhythmic agents, antibiotics (including penicillins),anticoagulants, antidepressants, antidiabetic agents, antiepileptics,antihistamines, antihypertensive agents, antimuscarinic agents,antimycobacterial agents, antineoplastic agents, immunosuppressants,antithyroid agents, antiviral agents, anxiolytic sedatives (hypnoticsand neuroleptics), astringents, beta-adrenoceptor blocking agents, bloodproducts and substitutes, cardiac inotropic agents, contrast media,corticosteroids, cough suppressants (expectorants and mucolytics),diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics(antiparkinsonian agents), haemostatics, immuriological agents, lipidregulating agents, muscle relaxants, parasympathomimetics, parathyroidcalcitonin and biphosphonates, prostaglandins, radio-pharmaceuticals,sex hormones (including steroids), anti-allergic agents, stimulants andanoretics, sympathomimetics, thyroid agents, vasodilators and xanthines.

The drugs are commercially available and/or can be prepared bytechniques known in the art.

2. Surface Stabilizers

Polymeric surface stabilizers useful herein physically adhere to thesurface of the nanoparticulate active agent, but do not chemically reactwith the drug or itself. Individually adsorbed molecules of the surfacestabilizer are essentially free of intermolecular cross-linkages.

The polymeric surface stabilizer is adsorbed on the surface of theactive agent in an amount sufficient to maintain an effective averageparticle size of less than about 1 micron. Two or more surfacestabilizers can be employed in the compositions and methods of theinvention.

Representative examples of suitable polymeric surface stabilizersinclude, but are not limited to polyvinylpyrrolidone (PVP), celluloseethers such as, but not limited to, hydroxypropyl cellulose,hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, and hydroxyethyl cellulose, polysaccharides such as, but notlimited to, dextrin, guar gum, starch, random copolymers of vinylacetate and vinyl pyrrolidone, such as Plasdone® S630 (ISP), Kollidone®VA 64 (BASF), polyvinyl alcohol, copolymers of vinylacetate andvinylalcohol.

Plasdone® S630 is a random copolymer of vinyl pyrrolidone and vinylacetate, in a 60:40 ratio. Other random copolymers of vinyl pyrrolidoneand vinyl acetate can also be used in the invention having, for example,ratios of vinyl pyrrolidone to vinyl acetate of 90:10, 80:20, or 50:50.Preferably, the random copolymer contains at least 50% vinylpyrrolidone.

The surface stabilizers are commercially available and/or can beprepared by techniques known in the art.

3. Nanoparticulate Drug/Surface Stabilizer Particle Size

As used herein, particle size is determined on the basis of the weightaverage particle size as measured by conventional particle sizemeasuring techniques well known to those skilled in the art. Suchtechniques include, for example, sedimentation field flow fractionation,dynamic and static light scattering, and disk centrifugation.

By “an effective average particle size of less than about 1 micron” itis meant that at least 90% of the active agent particles have a particlesize of less than about 1 micron when measured by the above techniques.In other embodiments, the nanoparticulate active agent compositions,comprising a nanoparticulate active agent and at least one polymericsurfactant, have an effective average particle size prior toincorporation in a solid dose form of less than about 800 nm, less thanabout 600 nm, less than about 400 nm, and less than about 200 nm.

Upon administration to a mammal, such as a human or animal, orreconstitution in an electrolyte solution, the solid dosenanoparticulate composition redisperses such that 90% of the activeagent particles have a particle size of less than about (1) 5 microns,when the nanoparticulate dispersion, prior to incorporation into a soliddose form, has an effective average particle size of less than about 1micron; (2) 4 microns, when the nanoparticulate dispersion, prior toincorporation into a solid dose form, has an effective average particlesize of less than about 800 nm; (3) 3 microns, when the nanoparticulatedispersion, prior to incorporation into a solid dose form, has aneffective average particle size of less than about 600 nm; (4) 2microns, when the nanoparticulate dispersion, prior to incorporationinto a solid dose form, has an effective average particle size of lessthan about 400 nm; and (5) 1 micron, when the nanocrystal dispersion,prior to incorporation into a solid dose form, has an effective averageparticle size of less than about 200 nm.

4. Other Pharmaceutical Excipients

Pharmaceutical compositions according to the invention may also compriseone or more binding agents, filling agents, lubricating agents,suspending agents, sweeteners, flavoring agents, preservatives, buffers,wetting agents, disintegrants, effervescent agents, and otherexcipients. Such excipients are known in the art.

Examples of filling agents are lactose monohydrate, lactose anhydrous,and various starches; examples of binding agents are various cellulosesand cross-linked polyvinylpyrrolidone, microcrystalline cellulose, suchas Avicel® PH101 and Avicel® PH102, microcrystalline cellulose, andsilicifized microcrystalline cellulose (SMCC).

Suitable lubricants, including agents that act on the flowability of thepowder to be compressed, are colloidal silicon dioxide, such as Aerosil®200, talc, stearic acid, magnesium stearate, calcium stearate, andsilica gel.

Examples of sweeteners are any natural or artificial sweetener, such assucrose, xylitol, sodium saccharin, cyclamate, aspartame, and accsulfameK. Examples of flavoring agents are Magnasweet® (trademark of MAFCO),bubble gum flavor, and fruit flavors, and the like.

Examples of preservatives are potassium sorbate, methylparaben,propylparaben, benzoic acid and its salts, other esters ofparahydroxybenzoic acid such as butylparaben, alcohols such as ethyl orbenzyl alcohol, phenolic compounds such as phenol, or quarternarycompounds such as benzalkonium chloride.

Suitable diluents include pharmaceutically acceptable inert fillers,such as microcrystalline cellulose, lactose, dibasic calcium phosphate,saccharides, and/or mixtures of any of the foregoing. Examples ofdiluents include microcrystalline cellulose, such as Avicel® PH101 andAvicel® PH102; lactose such as lactose monohydrate, lactose anhydrous,and Pharmatose® DCL21; dibasic calcium phosphate such as Emcompress®;mannitol; starch; sorbitol; sucrose; and glucose.

Suitable disintegrants include corn starch, potato starch, maize starch,and modified starches, croscarmellose sodium, crosspovidone, sodiumstarch glycolate, and mixtures thereof.

Examples of effervescent agents are effervescent couples such as anorganic acid and a carbonate or bicarbonate. Suitable organic acidsinclude, for example, citric, tartaric, malic, fumaric, adipic,succinic, and alginic acids and anhydrides and acid salts. Suitablecarbonates and bicarbonates include, for example, sodium carbonate,sodium bicarbonate, potassium carbonate, potassium bicarbonate,magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, andarginine carbonate. Alternatively, only the acid component of theeffervescent couple may be present.

5. Concentration of Nanoparticulate Drug, Surface Stabilizers and DOSS

The relative amount of drug, one or more polymeric surface stabilizers,and DOSS can vary widely. The optimal amount of the polymeric surfacestabilizers can depend, for example, upon the particular drug selected,the equivalent hydrophilic lipophilic balance (HLB) of the drug, themelting point, cloud point, and water solubility of the polymericsurface stabilizer, and the surface tension of water solutions of thestabilizer, etc.

The concentration of the one or more polymeric surface stabilizers canvary from about 0.01 to about 90%, from about 1 to about 75%, from about10 to about 60%, or from about 10 to about 55% by weight based on thetotal combined dry weight of the drug substance and surface stabilizer,not including other excipients.

The concentration of the drug can vary from about 99.8% to about 0.1%,from about 80% to about 5.0%, or from about 50% to about 10% by weightbased on the total combined dry weight of the drug and polymeric surfacestabilizer, not including other excipients.

The concentration of DOSS can vary from about 0.1 to about 20%, and fromabout 1 to about 10%, based on the total dry weight of the drug, surfacestabilizer, and DOSS, not including other excipients.

B. Methods of Making Nanoparticulate Formulations

The nanoparticulate drug compositions can be made using, for example,milling or precipitation techniques. Exemplary methods of makingnanoparticulate compositions are described in the '684 patent.

1. Milling to Obtain Nanoparticulate Drug Dispersions

Milling of aqueous drug dispersions to obtain a nanoparticulatedispersion comprises dispersing poorly soluble drug particles in aliquid dispersion medium, followed by applying mechanical means in thepresence of grinding media to reduce the particle size of the drug tothe desired effective average particle size. The drug particles can bereduced in size in the presence of at least one polymeric surfacestabilizer and/or DOSS. Alternatively, the drug particles may becontacted with one or more polymeric surface stabilizers and/or DOSSafter attrition. Other compounds, such as a diluent, can be added to thedrug/surface stabilizer composition during the size reduction process.Dispersions can be manufactured continuously or in a batch mode. Theresultant nanoparticulate drug dispersion can be utilized in soliddosage formulations, such as controlled release dosage formulations,solid dose fast melt formulations, aerosol formulations, tablets,capsules, etc.

2. Precipitation to Obtain Nanoparticulate Drug Compositions

Another method of forming the desired nanoparticulate composition is bymicroprecipitation. This is a method of preparing stable dispersions ofpoorly soluble drugs in the presence of one or more polymeric surfacestabilizers and one or more colloid stability enhancing surface activeagents free of any trace toxic solvents or solubilized heavy metalimpurities. Such a method comprises, for example: (1) dissolving thepoorly water-soluble drug in a suitable solvent; (2) adding theformulation from step (1) to a solution comprising at least onepolymeric surface stabilizer and DOSS to form a solution; and (3)precipitating the formulation from step (2) using an appropriatenon-solvent. The method can be followed by removal of any formed salt,if present, by dialysis or diafiltration and concentration of thedispersion by conventional means. The resultant nanoparticulate drugdispersion can be dried and used in a solid dose composition.

3. Methods of Drying Nanoparticulate Dispersions

The nanoparticulate liquid dispersion formed by either milling orprecipitation can be dried prior to formulating the composition into asolid dose form for administration.

Powders comprising nanoparticulate drug can be made by spray-dryingaqueous dispersions of a nanoparticulate drug, polymeric surfacestabilizer, and DOSS to form a dry powder which consists of aggregateddrug/polymeric surface stabilizer/DOSS nanoparticles. Alternatively, theaqueous dispersion of drug, polymeric surface stabilizer, and DOSS cancontain a dissolved diluent, such as lactose or mannitol, which whenspray dried forms diluent particles, each of which contains at least oneembedded drug nanoparticle combined with a polymeric surface stabilizerand DOSS.

Nanoparticulate drug dispersions can also be freeze-dried to obtainpowders suitable for formulation into solid dose forms. Such powderscomprise aggregated nanoparticulate drug particles having a polymericsurface stabilizer and DOSS. Freeze dried powders can also be obtainedby freeze drying aqueous dispersions of drug, polymeric surfacestabilizer, and DOSS, which additionally contain a dissolved diluentsuch as lactose or mannitol. In these instances the freeze dried powdersconsist of particles of diluent, each of which contains at least oneembedded drug nanoparticle combined with a polymeric surface stabilizerand DOSS.

Other known methods of processing liquid dispersions, and which can beemployed in the present invention, include granulation, including butnot limited to high shear granulation, fluid bed granulation, rotogranulation, and melt granulation. Additional methods such as spraycoating and extrusion spherization can also be used. Any otherconventional method for drying or otherwise processing a liquiddispersion can also be used in the invention.

C. Methods of Using Nanoparticulate Drug Formulations Comprising One orMore Polymeric Surface Stabilizers and DOSS

The solid dose nanoparticulate compositions of the present invention canbe administered to humans and animals in any pharmaceutically acceptablemanner, such as orally, rectally, pulmonary, intravaginally, locally(powders, ointments or drops), or as a buccal or nasal spray. Soliddosage forms for oral administration include capsules, tablets, pills,powders, pellets, and granules. In such solid dosage forms, thenanoparticulate drug is admixed with at least one of the following: (a)one or more inert excipients (or carrier), such as sodium citrate ordicalcium phosphate; (b) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, and silicic acid; (c) binders, suchas carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose and acacia; (d) humectants, such as glycerol; (e) disintegratingagents, such as agar—agar, calcium carbonate, potato or tapioca starch,alginic acid, certain complex silicates, and sodium carbonate; (f)solution retarders, such as paraffin; (g) absorption accelerators, suchas quaternary ammonium compounds; (h) wetting agents, such as cetylalcohol and glycerol monostearate; (i) adsorbents, such as kaolin andbentonite; and (j) lubricants, such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. For capsules, tablets, and pills, the dosage forms may alsocomprise buffering agents.

Actual dosage levels of the drug in the nanoparticulate compositions ofthe invention may be varied to obtain an amount of active ingredientthat is effective to obtain a desired therapeutic response for aparticular composition and method of administration. The selected dosagelevel therefore depends upon the desired therapeutic effect, the routeof administration, the potency of the drug, the desired duration oftreatment, and other factors.

The following examples are given to illustrate the present invention. Itshould be understood, however, that the invention is not to be limitedto the specific conditions or details described in these examples.Throughout the specification, any and all references to a publiclyavailable document, including a U.S. patent, are specificallyincorporated by reference.

EXAMPLE 1

The purpose of this example was to compare the redispersion propertiesof various solid dose nanoparticulate ketoprofen compositions in whichDOSS is added to a nanoparticulate dispersion following milling andspray drying (rather than during the milling process). Ketoprofen. alsoknown as m-benzoylhydratopic acid, is a nonsteroidal anti-inflammatoryanalgesic.

A ketoprofen nanoparticulate dispersion was prepared, having 15%ketoprofen, 1.5% PVP K29/32, and 0.075% SLS. The dispersion was preparedusing a Dyno®-Mill (Type: KDL; Mfg.: Willy A Bachofen AG, Basel,Switzerland) equipped with a 150 cc batch chamber using a 500 μm millingmedia of type Polymill500® for 2 hrs at 10° C.

The ketoprofen nanoparticulate dispersion (ketoprofen NCD) was thenspray dried with various excipients, as shown in Table 1, using a BüchiMini Spray Dryer B-191 (Büchi Switzerland). Following spray drying, theredispersion properties of each spray dried ketoprofen powder weretested by measuring the ketoprofen particle size following redispersionand dilution with saturated ketoprofen solution, without sonication andfollowing 1 minute sonication. Particle size was measured using a HoribaLA910 particle sizer. The results of the redispersion tests are alsoshown in Table 1, below.

TABLE 1 Redispersion Comparison of Nanoparticulate Ketoprofen SprayDried Powder Redispersed Particle Size (nm) Com- (No sonication/1 min.sonication) posi- % under tion Formula Mean D90* 1000 nm A no additives3801/3725 7697/7152 12.8/12.8 B Drug:mannitol 6836/4050 15415/1117341.8/52.2 1:1.2 C Drug:Mannitol:DOSS 1860/1055 8785/453  84.6/90.11:1.2:0.08 D Drug:Maltrin150** 20665/6104  38879/14479  9.2/26.6 1:1.2 EDrug:Mannitol:DOSS 17149/2737  72756/10229 55.4/75.0 1:0.6:0.08 FDrug:Xylitol 11241/5277  43502/12536 65.0/67.8 1:1 G Drug:Xylitol:DOSS1936/501  390/269 90.2/95.6 1:1:0.08 H Drug:Mannitol:DOSS 4069/194415113/8313  72.6/80.0 1:1:0.08 I Drug:Xylitol:DOSS 11469/2168 42333/7702  64.1/75.2 1:1:0.02 J Drug:Mannitol:DOSS 2963/200410800/8011  72.2/77.5 1:1:0.08 K Drug:Xylitol:DOSS 654/332 273/25195.0/98.2 1:0.75:0.08 *90% of the particles are below this size.**maltodextrin

The results dramatically show the effect DOSS has on theredispersibility of the spray dried nanoparticulate ketoprofencomposition. Following redispersion, less than 13% of the ketoprofenparticles of Composition A, lacking any additives (i.e., just spraydried ketoprofen NCD), had a particle size of less than a micron.Similarly, following redispersion less than 52.2% (following sonication)of the ketoprofen particles of Composition B, containing only mannitolas an additive, had a particle size of less than a micron. In contrast,following redispersion 90.1% (following sonication) of the ketoprofenparticles of Composition C, containing mannitol and DOSS as additives,had a particle size of less than a micron. Thus, DOSS resulted in a 75%increase in the amount of particles having a particle size of under 1micron following redispersion. This is significant as smaller drugparticles result in greater bioavailability of the drug.

The amount of DOSS in relation to other excipients also affects theredispersion properties of the solid dose nanoparticulate drugcomposition. Thus, by varying the amount of DOSS and other excipients,redispersion of a solid dose nanoparticulate composition can beoptimized. For example, Composition C, having a Drug:Mannitol:DOSS ratioof 1:1.2:0.08 showed 90.1% of the ketoprofen particles (followingsonication) having a particle size of less than 1 micron followingredispersion. However, Composition E, having a Drug:Mannitol:DOSS ratioof 1:0.6:0.08, showed 75.0% of the ketoprofen particles (followingsonication) having a particle size of less than 1 micron followingredispersion; Compositions H and J, having a Drug:Mannitol:DOSS ratiosof 1:1:0.08, showed 80.0% and 77.5%, respectively, of the ketoprofenparticles (following sonication) having a particle size of less than 1micron following redispersion.

Similar results were obtained with spray dry excipients other thanmannitol. For example, Composition F, having a Drug:Xylitol ratio of1:1, showed 67.8% of the ketoprofen particles (following sonication)having a particle size of less than 1 micron following redispersion. Incontrast, Compositions G and K, having Drug:Xylitol:DOSS ratios of1:1:0.08 and 1:0.75:0.08, respectively, showed 95.6% and 98.2%,respectively, of the ketoprofen particles (following sonication) havinga particle size of less than 1 micron following redispersion. This is anincrease of 41% (Composition G) and 45% over the results obtained withComposition F, lacking DOSS.

This example demonstrates the effectiveness of adding DOSS to form ahighly redispersible solid dose nanoparticulate composition, when DOSSis added following milling but before spray drying of thenanoparticulate dispersion. Other examples demonstrate the addition ofDOSS to the nanoparticulate dispersion during milling. Thus, the time ofaddition of DOSS during preparation of the pharmaceutical composition isnot critical to the goal of obtaining a highly redispersiblecomposition.

EXAMPLE 2

The purpose of this example was to evaluate the redispersion propertiesof a solid dose nanoparticulate ketoprofen composition comprising DOSSand a polymeric stabilizer in an electrolyte solution. This examplediffers from Example 1 in that DOSS is added directly to thenanoparticulate dispersion (NCD) during milling, followed by preparationof a solid dose composition.

A ketoprofen nanoparticulate dispersion was prepared, having thecomposition 5% ketoprofen, 1.% PVP K29/32, and 0.2% DOSS. The dispersionwas prepared using a Dyno®-Mill (Type: KDL; Mfg.: Willy A Bachofen A G,Basel Switzerland) equipped with a 150 cc batch chamber using a 500 μmmilling media of type Polymill500® for 2 hrs at 10° C.

The ketoprofen nanoparticulate dispersion (ketoprofen NCD) was thenspray dried with mannitol, with a drug to mannitol ratio of 1:1 using aBüchi Mini Spray Dryer B-191 (Büchi Switzerland). The redispersionproperties of the spray dried ketoprofen in water are shown below inTable 2.

TABLE 2 Redispersion Properties of Ketoprofen Spray Dried NCD ContainingDOSS in Water Mean Mean D₅₀ D₅₀ D₉₀ D₉₀ Time (no (1 min. (1 min. (no (1min. (no (days) sonication) sonication) somication) sonication)sonication) sonication) 0 118 121 105 107 192 198 1 152 163 144 155 219233 All measurements are in nanometers (nm).

The results of the redispersion test show excellent redispersion of thespray dried nanoparticulate ketoprofen composition comprising DOSS.

The redispersion properties of the same spray dried ketoprofencomposition were then tested in electrolyte solutions, which mimic theconditions found in the human gastrointestinal tract. The results ofthese tests are shown in Table 3, below.

TABLE 3 Redispersion Properties of Ketoprofen Spray Dried NCD ComprisingDOSS in an Electrolyte Solution 1 min. 1 min. Electrolyte no sonic. No.sonic. No. sonic. sonic. sonic. No. sonic. Conc. (M) Type Mean Small %Large % Mean Small % Large % 0 — 172 100 0 182 100 0 0.001 HCl 535 97 3166 100 0 0.01 HCl 176 100 0 188 100 0 0.1 HCl 17756 2 98 5908 8 920.001 NaCl 178 100 0 191 100 0 0.01 NaCl 151 100 0 163 100 0 0.1 NaCl186 100 0 204 100 0 All particle sizes are in nanometers (nm).

“Small” particles are defined as those below 1 micron (1000 nm) and“large” particles are those above 1 micron. Electrolyte concentrationsof 0.001 HCl, 0.01 HCl, and 0.1 HCl correspond to pH 3, pH 2, and pH 1,respectively. In the stomach, the pH ranges from slightly less than 2(but typically greater than 1) up to 4 or 5. In the small intestine thepH can range from 4 to 6, and in the colon it can range from 6 to 8.Thus, a 0.01 N HCl concentration simulates typical acidic conditionsfound in the stomach. 0.1 M NaCl simulates the electrolyte concentrationfound throughout the body, including the intestine.

The results show that under acidic to neutral pH conditions, thenanoparticulate ketoprofen solid dose composition showed excellentredispersion properties, with 100% of the nanoparticulate particleshaving a redispersed particle size of less than 1 micron. In addition,under all but the most acidic conditions of 0.1 M HCl (which are nottypically representative of human gastric pH), the nanoparticulateketoprofen solid dose composition showed excellent redispersionproperties, with almost 100% of the nanoparticulate particles having aredispersed particle size of less than 1 micron.

EXAMPLE 3

The purpose of this example was to evaluate the redispersion propertiesof a solid dose nanoparticulate MAP kinase inhibitor compositioncomprising DOSS and a polymeric stabilizer in electrolyte solutions.

5% (w/w) of Compound A, a MAP kinase inhibitor, 1% Plasdone® S630, and0.2% DOSS were milled using a Dyno®-Mill (Type: KDL; Mfg.: Willy ABachofen A G, Basel Switzerland) equipped with a 150 cc batch chamberusing a 500 μm milling media of type Polymill500® for 3 hrs at 10° C.

The nanoparticulate MAP kinase inhibitor dispersion (NCD) was then spraydried at a drug to mannitol ratio of 1:1 using a Büchi Mini Spray DryerB-191 (Büchi Switzerland). The redispersion properties of the spraydried MAP kinase inhibitor in electrolyte solutions are shown below inTable 4 and in FIG. 1. A Horiba LA910 particle sizer was used to measureparticle size. “Small” particles were defined as those below 1 micronand “large” particles were defined as those above 1 micron.

TABLE 4 Redispersion Properties of a MAP Kinase Inhibitor Spray DriedNCD Comprising DOSS and a Polymeric Stabilizer in an ElectrolyteSolution 1 min. 1 min. Electrolyte no sonic. No. sonic. No.sonic. sonic.sonic. No. sonic. Conc. (M) Type Mean Small % Large % Mean Small % Large% 0 — 99 100 0 99 100 0 0.001 HCl 100 100 0 100 100 0 0.01 HCl 105 100 0106 100 0 0.1 HCl 4708 23 77 1901 52 48 0.001 NaCl 103 100 0 103 100 00.01 NaCl 101 100 0 101 100 0 0.1 NaCl 105 100 0 105 100 0 All particlesizes are in nanometers (nm).

The results show that the solid dose nanoparticulate MAP kinaseinhibitor composition, comprising DOSS and a polymeric stabilizer,showed excellent redispersion in all tested electrolyte mediarepresentative of in vivo conditions. Even at a higher acidconcentration of 0.1 N HCl, the composition showed over 50% of the drugparticles of the composition having a small particle size following 1minute of sonication.

EXAMPLE 4

The purpose of this example was to evaluate the redispersion propertiesof a solid dose nanoparticulate angiogenesis inhibitor compositioncomprising DOSS and a polymeric stabilizer, which has been spraygranulated with various excipients, in water and in electrolytesolutions.

Nanocrystalline dispersions (NCD) of an angiogenesis inhibitor, CompoundC, were made by milling the ingredients shown for each composition inTable 7. Samples A and B were milled on a Netzch Mill (Netzsch Inc.,Exton, Pa.), having a LMZ 2L chamber, for 11 hrs. 500 micron PolyMillmedia was used. Processing temperatures ranged from 11.6° C. to 27.4° C.Samples C-E were milled on a Dyno® Mill, having a 150 cc chamber, at atemperature of 10° C. for 3 hours, also using 500 micron PolyMill media.

Following milling, the additives listed in Table 5 were added to thenanoparticulate dispersion until dissolved, followed by spraying of thedispersion over a fluidized mannitol excipient, also provided in Table5, to form a solid dose composition. A Glatt GPCG-1 fluid bed processor(Glatt Air Technologies, Inc., Ramsey, N.J.) was used for this process.

TABLE 5 Spray Granulated Nanoparticulate Angiogenesis InhibitorCompositions Particle Size of Nano- Fluidized Sample Formula crystalDispersion (nm) Additives Mannitol A 15% Drug + 3.75% mean 105 nm; Drugmannitol Pearlitol ® SD200 PVP K29/32 and D₉₀ of 167 nm ratio of 1:0.750.15% SLS B 15% Drug + 3.75% mean 105 nm; Drug mannitol Pearlitol ®SD200 PVP K29/32 and D₉₀ of 167 nm ratio of 1:0.75 0.15% SLS C 15%Drug + 3.75% mean of 101 nm; Drug mannitol Mannitol 35 PVP K29/32, 0.15%D₉₀ of 165 nm ratio of 1:0.75 SLS, and 0.1% sodium ascorbate D 15%Drug + 3.75% mean of 101 nm; Drug:mannitol Mannitol 35 PVP K29/32, 0.15%D₉₀ of 165 nm ratio of 1:0.75 SLS, and 0.1% sodium ascorbate E 15%Drug + 3.75% mean of 101 nm; Drug:mannitol Mannitol 35 PVP K29/32, 0.15%D₉₀ of 165 nm ratio of 1:0.75 and SLS, and 0.1% stabilizer DOSS sodiumascorbate ratio of 1:0.2

Each composition A-E, comprising drug/excipient granules, was thenmilled to a uniform particle size in a Quadro Comill (Model 193; alsocalled a cone mill, which comprises fixed stationary screens and arotating impeller), to produce Compositions A2-E2. The milling processcomprised passing the powder through the mill (one pass through, about2-5 minutes).

The redispersibility, in water and various electrolyte solutions, wasthen measured for the solid dose nanoparticulate angiogenesiscompositions, both Compositions A-E (unmilled) and A2-E2 (milled), asshown in Table 6.

TABLE 6 Redispersibility of Spray Granulated NanoparticulateAngiogenesis Inhibitor Compositions (Milled and Unmilled GranulateCompositions) No Sonication 1 Min. Sonication Redisp. Mean D90 % UnderMean D90 % Under Composition Media (nm) (nm) 1000 nm (nm) (nm) 1000 nm Awater 5265 11776 26.2 1440 4717 70.8 (unmilled) 0.01 N HCl 12160 272449.4 3034 6997 36.1 0.01 M NaCl 7487 15324 11.6 2274 6504 57.6 A2 water5777 12463 23.0 2538 7547 62.9 (milled) 0.01 N HCl 58519 236602 5.3 35737929 30 0.01 M NaCl 8341 17698 11 1975 5366 54.9 B water 8222 18365 18.54368 9033 51.5 (unmilled) 0.01 N HCl 83643 264545 4.8 4238 9458 26.30.01 M NaCl 14863 33139 8 2579 6561 45.8 B2 water 18897 55523 14.2 26917294 50 (milled) 0.01 N HCl 44037 103747 4.1 5161 11771 22.4 0.01 M NaCl13514 29820 6.8 2547 6163 42.1 C water 3124 8088 46.9 422 645 93.4(unmilled) 0.01 N HGl 6713 14117 16.6 2471 6285 47 0.01 M NaCl 4103 942630.6 904 3006 80.4 C2 water 3150 8427 49 1071 3602 83.6 (milled) 0.01 NHCl 8728 19180 17.1 3039 7626 43.3 0.01 M NaCl 4544 9896 25.5 1278 434575 D water 3094 7865 44.8 342 569 97.3 (unmilled) 0.01 N HCl 9630 2169714.8 2762 7043 45.3 0.01 M NaCl 4295 8561 20.6 1475 5034 73.6 D2 water2162 5885 54.4 295 488 98.7 (milled) 0.01 N HCl 8885 20181 16.9 19825087 51.7 0.01 M NaCl 4410 8710 19 1066 3420 75.9 E water 2186 7520 69.9384 614 98.3 (unmilled) 0.01 N HCl 2161 7812 73.4 297 492 99 0.01 M NaCl2544 8755 68.1 357 588 98.5 E water 2711 9141 66.6 436 672 93.6 (milled)0.01 N HCl 2014 7608 75.9 291 483 99.1 0.01 M NaCl 2203 8075 74.1 292484 99

Only Sample E comprises DOSS. The redispersibility results showed thatonly this sample showed substantially improved redispersion inelectrolyte media, with a redispersibility of 99.1% in 0.01 N HCl and99% in 0.01 M NaCl. In contrast, Samples A-D showed redispersibility in0.01 N HCl of from 22.4% (Sample B2) to 51.7% (Sample D2), and aredispersibility in 0.01 N HCl of from to 42.1% (Sample B2) to 80.4%(Sample C). The results are dramatic as the only difference betweenSample E and Samples C and D was the presence (Sample E) or absence(Samples C and D) of DOSS.

The results demonstrate the dramatically superior redispersibilityproperties of a solid dose nanoparticulate formulation comprising DOSS.

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the methods and compositionsof the present invention without departing from the spirit or scope ofthe invention. Thus, it is intended that the present invention cover themodifications and variations of this invention provided they come withinthe scope of the appended claims and their equivalents.

We claim:
 1. A nanoparticulate dispersion comprising: (a) a poorlysoluble active agent; (b) at least one polymeric surface stabilizeradsorbed on the surface of the active agent; and (c) about 0.1% to about20% w/w of dioctyl sodium sulfosuccinate (DOSS), wherein the effectiveaverage particle size of the poorly soluble active agent in thenanoparticulate dispersion is less than about 1 micron.
 2. Thedispersion of claim 1, wherein the active agent is present in an amountof about 99.8% to about 0.1% (w/w).
 3. The dispersion of claim 1,wherein the active agent is present in an amount of about 80% to about5% (w/w).
 4. The dispersion of claim 1, wherein the active agent ispresent in an amount of about 50% to about 10% (w/w).
 5. The dispersionof claim 1, wherein the at least one polymeric surface stabilizer ispresent in an amount of about 0.01% to about 90% (w/w).
 6. Thedispersion of claim 1, wherein the at least one polymeric surfacestabilizer is present in an amount of about 1% to about 75% (w/w). 7.The dispersion of claim 1, wherein the at least one polymeric surfacestabilizer is present in an amount of about 10% to about 60% (w/w). 8.The dispersion of claim 1, wherein DOSS is present in an amount of about1% to about 10% (w/w).
 9. The dispersion of claim 1, wherein theeffective average particle size of the nanoparticulate dispersion isless than about 800 nm.
 10. The dispersion of claim 1, wherein theeffective average particle size of the nanoparticulate dispersion isless than about 600 nm.
 11. The dispersion of claim 1, wherein theeffective average particle size of the nanoparticulate dispersion isless than about 400 nm.
 12. The dispersion of claim 1, wherein theeffective average particle size of the nanoparticulate dispersion isless than about 200 nm.
 13. The dispersion of claim 1, wherein theactive agent is selected from the group consisting of a crystallinephase, a semi-crystalline phase, and an amorphous phase.
 14. Thedispersion of claim 1, wherein the active agent is selected from thegroup consisting of proteins, peptides, nucleotides, anti-obesity drugs,nutraceuticals, corticosteroids, elastase inhibitors, analgesics,anti-fungals, oncology therapies, anti-emetics, analgesics,cardiovascular agents, anti-inflammatory agents, anthelmintics,anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants,antidiabetic agents, antiepileptics, antihistamines, antihypertensiveagents, antimuscarinic agents, antimycobacterial agents, antineoplasticagents, immunosuppressants, antithyroid agents, antiviral agents,anxiolytics, sedatives, astringents, beta-adrenoceptor blocking agents,blood products and substitutes, cardiac inotropic agents, contrastmedia, corticosteroids, cough suppressants, diagnostic agents,diagnostic imaging agents, diuretics, dopaminergics, haemostatics,immuriological agents, lipid regulating agents, muscle relaxants,parasympathomimetics, parathyroid calcitonin and biphosphonates,prostaglandins, radio-pharmaceuticals, sex hormones, anti-allergicagents, stimulants and anoretics, sympathomimetics, thyroid agents,vasodilators, and xanthines.
 15. The dispersion of claim 1, wherein theactive agent is ketoprofen.
 16. The dispersion of claim 1, wherein theactive agent is a MAP kinase inhibitor.
 17. The dispersion of claim 1,wherein the active agent is an angiogenesis inhibitor.
 18. Thedispersion of claim 1, wherein the at least one polymeric surfacestabilizer is selected from the group consisting ofpolyvinylpyrrolidone, cellulose ethers, polysaccharides, randomcopolymers of vinyl acetate and vinyl pyrrolidone, polyvinyl alcohol,and copolymers of vinyl acetate and vinyl alcohol.
 19. The dispersion ofclaim 18, wherein the at least one polymeric surface stabilizer isselected from the group consisting of hydroxypropyl cellulose,hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, dextrin, guar gum, starch, and acopolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a massproportion of 3:2.
 20. A pharmaceutical composition comprising thedispersion of claim 1, and one or more pharmaceutically acceptableexcipients.
 21. A method of making a nanoparticulate dispersioncomprising: (a) dispersing particles of a poorly soluble active agent ina liquid dispersion medium; and (b) applying mechanical means in thepresence of grinding media to reduce the effective average particle sizeof the active agent in the liquid dispersion medium to less than about 1micron, wherein at least one polymeric surface stabilizer and dioctylsodium sulfosuccinate are added to the liquid dispersion medium beforeor after milling.
 22. The method of claim 21, wherein the active agentis present in an amount of about 99.8 to about 0.1% (w/w).
 23. Themethod of claim 21, wherein the at least one polymeric surfacestabilizer is present in an amount of about 0.01% to about 90% (w/w).24. The method of claim 21, wherein DOSS is added in an amount of about0.1% to about 20% (w/w).
 25. The method of claim 21, wherein DOSS isadded in an amount of about 1.0% to about 10% (w/w).
 26. The method ofclaim 21, wherein the active agent is selected from the group consistingof a crystalline phase drug, a semi-crystalline phase drug, and anamorphous phase drug.
 27. The method of claim 21, wherein the effectiveaverage particle size of the resultant nanoparticulate dispersion isless than about 800 nm.
 28. The method of claim 21, wherein theeffective average particle size of the resultant nanoparticulatedispersion is less than about 600 nm.
 29. The method of claim 21,wherein the effective average particle size of the resultantnanoparticulate dispersion is less than about 400 nm.
 30. The method ofclaim 21, wherein the effective average particle size of thenanoparticulate dispersion is less than about 200 nm.
 31. The dispersionof claim 1, wherein the active agent is selected from the groupconsisting of ketoprofen, a MAP kinase inhibitor, and an angiogenesisinhibitor.
 32. The pharmaceutical composition of claim 20, wherein theactive agent is selected from the group consisting of ketoprofen, a MAPkinase inhibitor, and an angiogenesis inhibitor.
 33. The method of claim21, wherein the active agent is selected from the group consisting ofketoprofen, a MAP kinase inhibitor, and an angiogenesis inhibitor.